UCSF

Many cancers utilize the programmed death ligand (PD-L1)/ programmed death-1 (PD-1) pathway to avoid T-cell mediated immune destruction. The fact that PD-L1 transcripts are found in a wide array of cancer cells, but only a fraction has detectable levels of protein, highlights the need to better understand the post-transcriptional regulation of PD-L1. Here, we find that high levels of PD-L1 mRNA but low levels of protein in PC-3 cells are not due to translational regulation or rapid degradation. Instead, PD-L1 is preferentially packaged and secreted in exosomes. Furthermore, exosomal PD-L1 travels through the ER and Golgi complex and reaches the cell surface before entering the endosome system. Afterwards, PD-L1 is packaged into ceramide-dependent intraluminal vesicles (ILVs), which are secreted as exosomes in a Rab27a-dependent manner. Strikingly, we discovered that exosomal PD-L1 is capable of suppressing T cell activity in a co-culture assay. These findings provide critical insights into the regulation of PD-L1 and identify a novel mechanism for its delivery to PD-1. The results of this thesis may lead to new druggable targets in the PD-L1/PD-1 pathway as well as better companion diagnostics to identify likely responders to anti-PD-1/PD-L1 therapies.